BPS2026 – Molecular mechanism of pain perception by regulation of receptor tyrosine kinase TrkA

Chronic pain is a global health concern that affects ∼20% of the adult population, with opioids commonly prescribed for pain relief. This reliance on opiates poses a significant risk as a driver for worldwide addiction and misuse, motivating the need for a safer and effective therapeutic strategy. The high-affinity binding of nerve growth factor (NGF) to the receptor tyrosine kinase TrkA is vital for neuronal growth, development, and maintenance (neurotrophic outcomes). This pathway activation also triggers chronic pain. Mutations in this signaling axis lead to neuronal defects and/or loss of pain perception as found in populations with hereditary sensory and autonomic neuropathies (HSAN). The molecular mechanism by which NGF regulates TrkA, and how mutations in HSAN bias TrkA signaling to result in different physiological outcomes (e.g., loss of pain perception), remains elusive. Our work utilizes single-molecule microscopy approaches, structural studies (cryo-EM), electrophysiology, and quantitative assays to investigate the differences between TrkA signaling under physiological conditions and in HSAN. We mechanistically demonstrate how certain TrkA:NGF signaling axis mutants disentangle the neurotrophic and nociceptive signaling pathways, laying the foundation for new directions in chronic pain management.